Antidepressant treatment is reputed to be associated with unwanted, excessive weight gain. Regulation of body weight is a complex problem and can result from increase caloric intake, decreased caloric expenditure, or both. In this proposal, based on preliminary findings, the major focus in primarily on caloric expenditure, however selected studies also address food preference and caloric intake. The working hypothesis is that antidepressant-induced weight gain in humans follow from a reduction in caloric expenditure. The proposed studies will dissect the effects of antidepressant drugs on metabolism and metabolic rate. Studies will be performed in depressed humans and in rats. In depressed inpatients hospitalized for 4 weeks, the effects of two antidepressants (desipramine and fluvoxamine) on metabolic rate will be compared. Data will also be obtained on caloric intake in treated subjects. The results should expose which drug type(s) induce a decline in metabolic rate and/or influence body weight. Studies in depressed outpatients will explore for metabolic changes in subjects treated for 4 or more months with imipramine. These studies will characterize the time-course of metabolic effects, and determine if reductions in metabolic rate observed after 2-4 weeks of treatment are sustained over longer periods. Finally, experiments will be pursued in rats to elucidate the mechanism(s) by which drug- induced changes in metabolism occur. In both humans and rats, the actual experiments involve measurements of metabolic rate by quantitation of oxygen inspiration and carbon dioxide expiration. Measurements in blood of key energy substrates and insulin will also be made, by chemical and radioimmunoassay techniques. These latter determinations will be an important complement to the metabolic rate determinations made using inspired and expired gases. Overall, the results of these studied should help to determine that portion of the depressed population susceptible to antidepressant-induced weight gain, and the pharmacologic and metabolic causes of their increase in body weight. The findings may therefore be useful in formulating a pharmacologic strategy that will avoid weight gain as a side- effect to antidepressant treatment.